Arylpyrazoles as leukotriene inhibitors

ABSTRACT

Compounds of Formula I ##STR1## useful in the treatment of inflammatory disorders.

This application claims the benefit of U.S. provisional application Ser.No. 60/031,957 filed Nov. 27, 1996.

This invention relates a series of arylpyrazoles, intermediates used intheir manufacture and pharmaceutical compositions containing them. Thecompounds are inhibitors of leukotrienes, particularly they inhibit5-lipoxygenase and may be used in a variety of inflammatory relateddisorders such as rheumatoid arthritis, asthma, hypersensitivity,myocardial ischemia, psoriasis and inflammatory bowel syndrome.

BACKGROUND OF THE INVENTION

Leukotrienes are a family of endogenous metabolites of arachidonic acidand play an integral role in regulating inflammatory events. Since theirdiscovery in the late seventies, many have worked to determine thebiosynthesis of leukotrienes with an eye toward mediating theinflammatory responses. The focus of much of this work concerned theenzymes used in leukotriene biosynthesis, particularly the first enzymein the cascade, 5-lipoxygenase. This work has produced a number of drugcandidates including the anti-asthmatic, zileuton, which is currently inclinical trials.

In the nineties, work surrounding the search for 5-lipoxygenaseinhibitors expanded with the discovery of the 5-lipoxygenase activatingprotein, FLAP. FLAP is a membrane protein which enhances the catalyticactivity of 5-lipoxygenase. Although the precise mechanism of thiscooperation is unknown, it has been shown that compounds which bind toFLAP, inhibit the action of 5 lipoxygenase in whole cell assays but areinactive in broken cell enzyme assays. This work has lead to a number ofinteresting compounds, including MK-0591, an anti-asthmatic agent.##STR2##

The compounds of the invention are potent 5-lipoxygenase inhibitors manyof which are significantly more potent in whole cell assays, than inbroken cell enzyme assays. Like other 5-lipoxygenase inhibitors thesecompounds are useful in the treatment of disease states associated withinhibition of leukotriene biosynthesis such as rheumatoid arthritis,asthma, hypersensitivity, myocardial ischemia, psoriasis andinflammatory bowel syndrome.

SUMMARY OF THE INVENTION

The inventions relates to novel compounds of the Formula I ##STR3##wherein: R₁, R₂, R₃, and R₄ are selected from the group consisting ofhydrogen, C₁₋₅ alkyl, C₁₋₅ alkoxy, phenyl, halo, hydroxy, C₁₋₅alkylsulfonyl, C₁₋₅ alkylthio, trihaloC₁₋₅ alkyl, amino, nitro and2-quinolinylmethoxy;

R₅ is selected from the group consisting of C₁₋₅ alkyl and R₇ where R₇is (CH₂)_(n) R₈ or (CH₂)_(n) CHR₈ R₉ where

n is 1 or 2;

R₈ is halo, oxy, carbonyl, hydroxy, oximino, carboxy, C₁₋₅alkoxycarbonyl, N--C₁₋₅ alkyl-N-hydroxy-amido;

R₉ is 4-(2-quinolinylmethoxy)phenyl;

R₆ is selected from the group consisting of hydrogen, C₁₋₅ alkyl andhalo;

with the proviso that if R₉ is present, R₁, R₂, R₃, and R₄ are otherthan 2-quinolinylmethoxy;

with the further proviso that if R₉ is absent one of R₁, R₂, R₃, and R₄is 2-quinolinylmethoxy;

and pharmaceutically acceptable salts therof.

An additional formula of the invention is Formula II ##STR4## wherein:R₁, R₂, R₃, and R₄ are selected from the groups consisting of hydrogen,C₁₋₅ alkyl, C₁₋₅ alkoxy, phenyl, halo, hydroxy, C₁₋₅ alkylsulfonyl, C₁₋₅alkylthio, trihaloC₁₋₅ alkyl, amino, nitro and 2-quinolinylmethoxy;

n is 1-3;

R₆ is selected from the group consisting of hydrogen, C₁₋₅ alkyl andhalo;

with the proviso that one of R₁, R₂, R₃, and R₄ is 2-quinolinylmethoxy

and pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of Formula I may be prepared as illustrated by thefollowing schemes. As illustrated by Scheme 1 to prepare a compoundwhere R₁ is H, R₂ is Cl, R₃ is hydrogen, R₄ is 2-quinolinylmethoxy, R₅is (CH₂)₂ CO₂ Et and R₆ is hydrogen, 3-5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-pyrazoloyl!propionic acid 1A isthe starting material. This starting material is prepared as describedin U.S. Pat. No. 4,826,868 which is hereby incorporated by reference.Acid 1A is treated with HBr to give the hydroxy derivative 1B. 1B may beesterified in the presence of ethanol and H₂ SO₄ at reflux over 16 h andgives the corresponding ester 1C. Treatment of 1C with2-(chloromethyl)quinoline and a base such as K₂ CO₃ in an inert solventsuch as acetone at reflux over 16 h gives 1D where R₁ is H, R₂ is Cl, R₃is hydrogen, R₄ is 2-quinolinylmethoxy R₅ is (CH₂)₂ CO₂ Et. ##STR5##

Compound 1D may be used to prepare other compounds of Formula 1 where R₅is (CH₂)₂ CO₂ -i-butyl, (CH₂)₃ OH and (CH₂)₂ CO₂ H, as illustrated byScheme 2. Compound 1D may be hydrolyzed using bases such as NaOH (1.5eq.) and alcohols such as ethanol to give the corresponding acid 2A.Treatment of 1D with 1M DIBAL (3 eq.) in an inert solvent at about 0° C.for 1-3 h gives the corresponding alcohol 2B. In addition, treatment of1D with 1M DIBAL/THF (3 eq.) in THF at 0° C. to room temperature overabout 16 h gives the isobutyl ester 2C. ##STR6##

Compounds synthesized by Scheme 2 can be used to prepare other compoundsof the invention. As illustrated by Scheme 3, treatment of the alcohol2B with triphosgene (ca. 0.5 eq.) and pyridine (ca. 1 eq.) CH₂ Cl₂ at 0°C. to room temperature for about 1 h, followed by treatment of theresulting mixture with N-methylhydroxylamine hydrochloride (2 eq.) andtriethylamine (2 eq.) from 0° C. to room temperature for about 16 hgives the corresponding chloride 3A and the corresponding carbamate 3B.In addition, alcohol 2B may be treated with triphosgene (ca. 0.5 eq.) inpyridine at 0° C. over 3 h, followed by treatment of the resultingmixture with N-methylhydroxylamine hydrochloride (4 eq.) andtriethylamine (4 eq.) in CH₂ Cl₂ at room temperature over 7 days to givethe corresponding carbonate 3C. Finally, oxidation of 2B with pyridiniumchlorochromate (2 eq.) at room temperature over about 2 h gives thecorresponding aldehyde 3D. ##STR7##

In order to prepare compounds where R₅ is (CH₂)₂ C(O)N(OH)CH₃, Scheme 4may be used. The acid, 2A, may be treated with carbonyldiimidazole (ca.1.2 eq.) in CH₂ Cl₂ at room temperature for about 1 h, followed bytreatment of the resulting mixture with N-methylhydroxylaminehydrochloride (ca. 1.2 eq.) and triethylamine (ca. 1.2 eq.) in CH₂ Cl₂at room temperature for about 4 days to give the hydroxamic acid 4A.Scheme 4 also illustrates the synthesis of compounds where R₅ is (CH₂)₂C(N)--OH. Aldehyde 3D is treated with N-hydroxylamine hydrochloride (3eq.) and sodium acetate (3 eq.) in EtOH at room temperature to refluxover 3 h to give the desired oxime 4B. ##STR8##

To prepare the compounds of Formula 1 where R₅ is CH₂ CH--(CO₂Me)-4-(2-quinolinmethoxy)phenyl), Scheme 5 may be used. Halide 5A(prepared via the method outlined in Scheme 3) is treated with NaH/THFand 1- 4-(2-quinolinmethoxy)phenyl!acetic acid methyl ester at 0° C. toroom temperature to give compound 5B. In order to prepare compoundswhere R₅ is (CH₂)₂ CH--(CO₂ Me)-4-(2-quinolinmethoxy)phenyl), halidessuch as 3A can be substituted for 5A in Scheme 5.

The ester group of 5B may be treated in the same manner as 1C, to givecompounds where R₈ is halo, oxy, hydroxy, oximino, carboxy and N--C₁₋₅alkyl-N-hydroxyamido ##STR9##

To prepare compound where R₅ is C₁₋₅ alkyl, Scheme 6 may be used. Thedione 6A is treated with an appropriately substituted hydrazinehydrochloride, 6B, in an alcoholic solvent at room temperature to givethe pyrazole 6C. This pyrazole may be treated with HBr, followed bycoupling with 2-(chloromethyl)quinoline as described in Scheme 1 to givethe desired compound 6D. Compound 6D may be used to prepared compoundswhere R₆ is halo. For example, treatment of 6D with NBS at roomtemperature for 16 h affords the bromide 6E. ##STR10##

All compounds of Formula I may be prepared using the aforementionedschemes. For example, most of the starting materials which lead todifferent aromatic substitution on the 1 and 5 pyrazole positions(analogs of 1C) are made from the acids described in U.S. Pat. No.4,826,868. However in order to make compounds where one of R₁, R₂, R₃ orR₄ are hydroxy, Scheme 7 may be used. An appropriately substitutedhydrazine, 7B is treated with1-(4-benzyloxyphenyl)-6-carboxyhexan-1,3-dione, 7A at room temperaturein an alcoholic solvent to give the pyrazole 7C. This compound isdebenzylated with 10% Pd/C to give the hydroxy acid 7D. This compoundmay be treated with 2-(chloromethyl)quinoline as described in Scheme 1to give 7E. ##STR11##

The preferred compositions of Formula I include compounds where:

R₁ and R₃ are: 4-halo, 4-(2-quinolinylmethoxy)phenyl, 4-hydroxy and C₁₋₅alkoxy;

R₇ is: (CH₂)_(n) R₈, where n is 2 and R₈ is carboxy, N--C₁₋₅alkyl-N-hydroxy-amido, C₁₋₅ alkoxycarbonyl; or (CH₂)_(n) R₈ R₉ where R₉is 4-(2-quinolinylmethoxy)phenyl;

R₆ is hydrogen and C₁₋₅ alkyl.

The compounds of the invention were evaluated for their ability toinhibit the production of the arachidonic acid product 5-HETE in brokenand whole cell models. Since this is the first step of leukotrienebiosynthesis, a reduction in the production of 5-HETE is directlyattributable to inhibition of 5-lipoxygenase, where the standardconcentration is 3.0 μM. If the IC₅₀ of the whole cell assay is smallerthan the IC₅₀ of the broken cell model, it is an indication that thecompounds are inhibiting the cooperation of FLAP and 5-lipoxygenase.

Rat basophilic leukemia cells (RBL-1; 5×10⁷ viable cells/mL) weredisrupted by homogenization on ice (four 20 sec bursts) with a Brinkmanpolytron. Complete cell breakage was verified microscopically. Thehomogenate was then centrifuged at 9,220×g for 48 minutes at 4° C. Thepellet was discarded and the supernatant was saved as the source ofenzymes. The supernatant was pre-incubated for five minutes at 37° C. inthe presence of 2 mM of CaCl₂ and compound or vehicle (1% DMSO). Theconversion of AA into products by CO and LO was initiated by adding 10μL (50 μCi) of 1-¹⁴ C-AA to each tube and incubated at 37° C. for 20minutes. The reaction was stopped by adjusting the pH of each sample to3 to 3.5 with 2M formic acid. Samples were extracted with three volumesof chloroform to isolate the products of 5-LO formed during thereaction. Fractions were dried under nitrogen, then resuspended in 40 μLof chloroform and spotted onto silica gel HL plates. The plates weredeveloped in A-9 solvent. The dried plates were analyzed using a BioscanImaging TLC scanner to determine the percentage of radiolabelled AAconverted to 5-HETE (LO product) in each sample. The percentage ofinhibition was calculated by:

     1-(5-HETE test)!/5-HETE control×100=% inhibition

The IC₅₀ was determined using a curve fit in Cricket Graph (ComputerAssociated), which provided the equation of the regressed line used inthe calculation.

The ability to inhibit 5-LO and CO in intact RBL-1 cells was alsoevaluated. RBL-1 cells were maintained in culture in minimal essentialmedium (Bio*Whittaker, Walkersville, Md.), containing 12.5% fetal calfserum, 10 mg/mL streptomycin, 10 I.U./mL penicillin G, 50 mg/mLgentamycin and 2 mM L-glutamine (Bio*Whittaker, Walkersville, Md.).Cells were collected by centrifugation, washed once in HBSS, andresuspended at a concentration of 1×10⁵ cells/mL. Cells were incubatedin the presence of vehicle or drug then centrifuged at 800×g for 10minutes at 4° C. The supernatant was removed by aspiration and the cellswere resuspended in 0.5 mL of HBSS. The reaction was started by theaddition of 20 μg/mL of calcium ionophore A 23187 (mixed calcium andmagnesium salts, Calbiochem, La Jolla Calif.) and allowed to proceed for15 minutes, then stopped by plunging the tubes into a slush ice bath.The conversion of AA to 5-LO products was initiated by the addition of10 μL (50 uCi) of 1-¹⁴ C-AA. Products were isolated by acidification andextraction, followed by thin layer chromatography analysis as describedabove. Radioactive areas corresponding to authentic 5-LO (5-HETE) and CO(PGD₂) products were quantitated by the Bioscan 2000 Imaging System andthe IC₅₀ was calculated as above.

The %inhibition and IC₅₀ values at a dose of 3 μM for representativecompounds are listed in Tables A and B

                                      TABLE A                                     __________________________________________________________________________     ##STR12##                                                                    QM = 2-quinolinylmethoxy                                                                             Isolated Enzyme                                                                         Whole Cell                                   Cpd #                                                                             R.sub.1                                                                           R.sub.3                                                                           R.sub.5    % Inhib.                                                                           IC.sub.50 μM                                                                    IC.sub.50 μM                              __________________________________________________________________________    1   4-Cl                                                                              4-QM                                                                              CH.sub.2 CO.sub.2 Et                                                                     29        13.4                                         2   4-Cl                                                                              4-QM                                                                              CH.sub.2 CO.sub.2 H                                                                      15        0.39                                         3   4-Cl                                                                              4-QM                                                                              (CH.sub.2).sub.2 OH                                                                      31        1.3                                          4   4-Cl                                                                              4-QM                                                                              (CH.sub.2).sub.2 Cl                                                                      55        5.3                                          5   4-Cl                                                                              4-QM                                                                              (CH.sub.2).sub.2 O.sub.2 CN(Me)OH                                                        93        1.1                                          7   4-Cl                                                                              4-QM                                                                              (CH.sub.2).sub.2 CON(Me)OH                                                               93   0.21 0.49                                         8   4-Cl                                                                              4-QM                                                                              (CH.sub.2).sub.2 CHO                                                                     49        3.2                                          9   4-Cl                                                                              4-QM                                                                              (CH.sub.2).sub.2 CH(N)OH                                                                 44        0.55                                         10  4-Cl                                                                              4-QM                                                                              (CH.sub.2).sub.2 CO.sub.2 iso-Bu                                                         34        1.5                                          11  4-Cl                                                                              4-QM                                                                              Me         32        6.5                                          12  4-Cl                                                                              4-QM                                                                              (CH.sub.2).sub.2 CO.sub.2 Et                                                             19        7.4                                          13  4-QM                                                                              4-OMe                                                                             (CH.sub.2).sub.2 CO.sub.2 H                                                              8         3.9                                          14  4-QM                                                                              4OMe                                                                              (CH.sub.2).sub.2 CO.sub.2 H                                                              24        2                                            15  4-Cl                                                                              4-QM                                                                              (CH.sub.2).sub.2 CO.sub.2 H                                                              0         5.2                                          16  4-QM                                                                              4OMe                                                                              (CH.sub.2).sub.2 CON(Me)OH                                                               87        0.54                                         17  4-QM                                                                              4-H (CH.sub.2).sub.2 CO.sub.2 Me                                                             19        not tested                                   18  4-QM                                                                              4-Cl                                                                              (CH.sub.2).sub.2 CO.sub.2 H                                                              0         not tested                                   19  4-QM                                                                              4-H (CH.sub.2).sub.2 CO.sub.2 H                                                              0         not tested                                   20  4-Cl                                                                              4-QM                                                                              (CH.sub.2).sub.3 OH                                                                      21        0.84                                         21  4-QM                                                                              4-Cl                                                                              (CH.sub.2).sub.2 CON(Me)OH                                                               15        not tested                                   22  4-Cl                                                                              4-QM                                                                              (CH.sub.2).sub.2 CON(Me)OH                                                               100       1                                            __________________________________________________________________________

                  TABLE B                                                         ______________________________________                                         ##STR13##                                                                                                 Whole                                                              Isolated Enzyme                                                                          Cell                                             Cpd # R.sub.1                                                                              R.sub.3 R.sub.8  % Inhib.                                                                             IC.sub.50 μM                                                                     IC.sub.50 μM                    ______________________________________                                        22    4-Cl   4-OMe   CO.sub.2 Me                                                                            35     47.5  0.63                               23    4-Cl   4-OMe   CON(Me)OH                                                                              73      5.3  0.52                               ______________________________________                                    

As indicated by tables A and B the compounds of Formula I may be used inpharmaceutical compositions to treat patients (humans and otherprimates) with inflammatory related disorders, in the same manner asknown 5-lipoxygenase inhibitors. The compounds can be administered byany parenteral route (intravenous, intraperitoneal, subcutaneous, dermalpatch), or by an oral route where the preferred route is oral and thedosage range is 1-25 mg/kg.

The pharmaceutical compositions can be prepared using conventionalpharmaceutical excipients and compounding techniques. Oral dosage formsmay be elixers, syrups, capsules tablets and the like. Where the typicalsolid carrier is an inert substance such as lactose, starch, glucose,methyl cellulose, magnesium sterate, dicalcium phosphate, mannitol andthe like; and typical liquid oral excipients include ethanol, glycerol,water and the like. All excipients may be mixed as needed withdisintegrants, diluents, granulating agents, lubricants, binders and thelike using conventional techniques known to those skilled in the art ofpreparing dosage forms. Parenteral dosage forms may be prepared usingwater or another sterile carrier.

Compounds of Formula I, may be isolated and used as theirpharmaceutically acceptable salts. Examples of such salts includehydrobromic, hydroiodic, hydrochloric, perchloric, sulfuric, maleic,fumaric, malic, tartatic, citric, benzoic, mandelic, methanesulfonic,hydroethanesulfonic, benzenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic andsaccharic.

The following representative examples are illustrative not limiting.Other embodiments which are included within the scope of this inventionwill be apparent to those skilled in the art of chemical synthesis andantiinflammatory agents.

EXAMPLES ##STR14## Example 1 Preparation of Ethyl5-(4-Chlorophenyl)-1-(4-(2-quinolyl)methoxy)phenyl)-pyrazol-3-yl!acetateCpd 1

Ethyl 5-(4-Chlorophenyl)-1-(4-hydroxyphenyl)pyrazol-2-yl!acetate (3.92g, 11 mmol), 2-(chloromethyl)quinoline.HCl (4.7 g, 1.5 eq.), K₂ CO₃(3.04 g, 1.5 eq.) and Nal (1.65 g, 1 eq.) were heated and stirred atreflux under N₂ for 5 days. The resulting mixture was concentrated invacuo, dispersed in ethyl acetate, H₂ O and 1N HCl. The resultingaqueous layer was extracted with several portions of ethyl acetate andthe combined organic extracts were dried (Na₂ SO₄) and concentrated invacuo. The residue was purified by column chromatography andrecrystallization to give the title compound as a white solid. mp122°-123° C. ##STR15##

Example 2 Preparation of 2-5-(4-Chlorophenyl)-1-(4-(2-quinolyl)methoxyphenyl)-pyrazol-3-yl!aceticacid Cpd 2

Cpd 1 (2.2 g, 4.4 mmol) and 2N NaOH (20 mL) were heated in EtOH toreflux under N₂. 3N HCl (30 mL) was added to the resulting mixture,which afforded a solid precipitate upon cooling. The off white solid wasisolated and dried in vacuo to give the title compound. mp 228°-30° C.##STR16##

Example 3 Preparation of 2-5-(4-Chlorophenyl)-1-(4-(2-quinolyl)methoxy)phenyl)-pyrazol-3-yl!ethanoCpd 3

Diisobutylaluminum hydride (DIBAL) (12 mL, 3 eq.) was added slowly to astirred solution of Cpd 1 (2.01 g, 4 mmol) in THF (25 mL) at 0° C. Afterthe addition, the mixture was allowed to warm to room temperature forabout 3 h and concentrated in vacuo. A portion of H₂ O (150 mL) wasadded and this aqueous layer was extracted with several portions ofethyl acetate. The combined organic extracts were dried, (Na₂ SO₄) andconcentrated in vacuo. The residue was recrystallized from ethyl acetateand hexanes to give the title compound as an off-white solid. mp130°-32° C. ##STR17##

Example 4 Preparation of 3-(2-Chloroethyl)-5-(4-chlorophenyl)-1-4-(2-quinolyl)methoxyphenyl!pyrazole Cpd 4

A solution of triphosgene (0.79 g, 2.8 mmol) in CH₂ Cl₂ (15 mL) wasadded to a stirred solution of Cpd 3 (2.4 g, 5 mmol) and pyridine (0.4mL 5 mmol) in CH₂ Cl₂ (30 mL). This mixture was stirred for 1 h at roomtemperature and concentrated in vacuo. The residue was added to amixture of methyl hydroxylamine hydrochloride (0.84 g, 2 eq.) andtriethylamine (1.4 mL, 2.0 eq.) in CH₂ Cl₂ (25 mL) at 0° C., and theresulting mixture was allowed to warm up to room temperature and stirredovernight. The reaction mixture was partitioned between H₂ O and ethylacetate and the resulting aqueous layer was washed with several portionsof ethyl acetate. The combined organic extracts were dried (Na₂ SO₄) andconcentrated in vacuo. The residue was purified by column chromatographyand recrystallization to give the title compound as an off-white solid.mp 105°-08° C. ##STR18##

Example 5 Preparation of 5-(4-Chlorophenyl)-3-2-(N-hydroxy-N-methylcarbamoyloxy)!ethyl!-1-4-(2-quinolyl)methoxyphenyl!pyrazole.0.05 Hydrate Cpd 5

The title compound was isolated from the purification (columnchromatography of Cpd 4 as a yellow oil. Rf.=0.73. ##STR19##

Example 6 Preparation of Di-2-{5-(4-Chlorophenyl)-1-4-(2-quinolyl)methoxyphenyl!-pyrazol-3-yl)ethylcarbonate Cpd 6

Cpd 3 (1.09 g, 2.4 mmol) and triphosgene (0.35 g, 1.2 mmol) in pyridine(20 mL) were combined at 0° C., stirred at room temperature for 3 h andconcentrated in vacuo. A solution of N-methylhydroxylamine (0.8 g, 4eq.) and triethylamine (1.34 mL, 4 eq.) in CH₂ Cl₂ (35 mL) was added tothe residue and the resulting mixture was stirred for 7 days at roomtemperature. The reaction was quenched with H₂ O (150 mL) and extractedwith several portions of CH₂ Cl₂. The combined organic extracts weredried (Na₂ SO₄) and purified by column chromatography using CH₂ Cl₂/MeOH as an eluent to give a brown oil.

IR (KBr cm⁻¹ 1744, 1514. ##STR20##

Example 7 Preparation of 3-{5-(4-Chlorophenyl)-N-hydroxy-N-methyl-1-4-(2-quinolyl)methoxyphenyl!pyrazol-3-yl}propanamide Cpd 7

Neat oxalyl chloride (0.29 mL, 3.3 mmol) in CH₂ Cl₂ (15 mL) was added toa solution of 3-5-(4-chlorophenyl)-1-(4-(2-quinolyl)methoxyphenyl)-pyrazol-3-yl!propionicacid (0.9 g, 3.3 mmol: prepared in the manner of Cpd 2) in CH₂ Cl₂ (30mL) at 0° C. This mixture was stirred at room temperature for 4 hconcentrated in vacuo and the residue was dissolved in CH₂ Cl₂ (25 mL).This solution was added to a solution of N-methylhydroxylaminehydrochloride (0.31 g, 3.72 mmol), and triethylamine (0.52 mL, 3.72mmol) in CH₂ Cl₂ (40 mL) at 0° C. and the resulting mixture was allowedto warm up to room temperature overnight. The reaction was quenched with1N HCl (50 mL) and extracted with several portions of CH₂ Cl₂. Thecombined organic layers were dried (Na₂ SO₄) and concentrated in vacuo.The residue was purified by column chromatography (ethyl acetate eluent)and recrystallization (ethyl acetate/CH₂ Cl₂) to give the title compoundas a white solid mp 130°-31° C. ##STR21##

Example 8 Preparation of 3-5-(4-Chlorophenyl)-1-(4-(2-quinolyl)methoxy)phenyl)-pyrazol-3-yl!propanalCpd 8

A mixture of 3-5-(4-chlorophenyl)-1-(4-(2-quinolyl)methoxy)phenyl)pyrazol-3-yl!propanol(6.46 g, 13.75 mmol: prepared in the manner of Cpd 3) and PCC (5.93 g,27.5 mmol) in CH₂ Cl₂ (30 mL) was stirred at room temperature for 2 h.The solvent was decanted and the precipitate was washed with severalportions of ethyl acetate. The combined organic washings were filteredthrough paper and a florisil column and finally concentrated in vacuo.The residue was purified by column chromatography (ethylacetate/hexanes) and recrystallizations from Et₂ O to give the titlecompound as a white solid. mp 85°-89° C. ##STR22##

Example 9 Preparation of 5-(4-Chlorophenyl)-3-oximino1-(4-(2-quinolyl)methoxy)phenyl)-pyrazol-3-yl!propanal.0.25 Hydrate Cpd9

A mixture of Cpd 8 (0.9 g, 1.9 mmol), hydroxylamine (0.79 g, 5.7 mmol)and sodium acetate (0.94 g, 5.7 mmol) in EtOH (20 mL) was stirred atroom temperature for 2 h and heated to reflux for 1 h. The mixture wasconcentrated in vacuo, quenched with H₂ O (250 mL) and extracted withseveral portions of ethyl acetate The combined organic extracts weredried and concentrated in vacuo to give an oil which crystallized uponstanding to give the title compound as a white solid. mp 139°-41° C.##STR23##

Example 10 3-{5-(4-Chlorophenyl)-N-hydroxy-N-methyl-1-4-(2-quinolyl)methoxyphenyl!pyrazol-3-yl}propionate Cpd 10

Diisobutylaluminum hydride (58.75 mL, 19.5 mmol) was added slowly to asolution of ethyl5-(4-Chlorophenyl)-1-(4-hydroxyphenyl)pyrazol-3-yl!propionate (10.0 g,19.5 mmol: prepared in the manner of Cpd 1) in THF (25 mL) at 0° C. Theresulting mixture was allowed to warm to room temperature and wasstirred overnight and concentrated in vacuo. The residue was cooled, H₂O (500 mL) was added and the mixture was extracted with several portionsof ethyl acetate. The combined extracts were dried and concentrated invacuo. The residue was purified by recrystallization from ether/hexaneto give the title compound as a white solid. mp 95°-97° C.

We claim:
 1. A compound selected from those of Formula I ##STR24##wherein: R₁, R₂, R₃, and R₄ are selected from the group consisting ofhydrogen, C₁₋₅ alkyl, C₁₋₅ alkoxy, phenyl, halo, hydroxy, C₁₋₅alkylsulfonyl, C₁₋₅ alkylthio, trihaloC₁₋₅ alkyl, amino, nitro and2-quinolinylmethoxy;R₅ is selected from the group consisting of C₁₋₅alkyl and R₇ where R₇ is (CH₂)_(n) R₈ or (CH₂)_(n) CHR₈ R₉ where n is 1or 2; R₈ is halo, oxy, carbonyl, hydroxy, oximino, carboxy, C₁₋₅alkoxycarbonyl, N--C₁₋₅ alkyl-N-hydroxy-amido; R₉ is4-(2-quinolinylmethoxy)phenyl; R₆ is selected from the group consistingof hydrogen, C₁₋₅ alkyl and halo; with the proviso that if R₉ ispresent, R₁, R₂, R₃, and R₄ are other than 2-quinolinylmethoxy; with thefurther proviso that if R₉ is absent one of R₁, R₂, R₃, and R₄ is2-quinolinylmethoxy;and pharmaceutically acceptable salts thereof.
 2. Acompound according to claim 1 wherein R₁ and R₃ are selected from4-halo, 4-(2-quinolinylmethoxy)phenyl, 4-hydroxy and C₁₋₅ alkoxy; R₇ isselected from (CH₂)_(n) R₈ ; where n is 2 and R₈ is selected fromcarboxy, N--C₁₋₅ alkyl-N-hydroxy-amido and C₁₋₅ alkoxycarbonyl; or(CH₂)_(n) R₈ R₉ where R₉ is 4-(2-quinolinylmethoxy)phenyl; R₆ isselected from hydrogen and C₁₋₅ alkyl.
 3. The compound according toclaim 1: Ethyl5-(4-Chlorophenyl)-1-(4-(2-quinolyl)methoxy)phenyl)-pyrazol-2-yl!acetate.4. The compound according to claim 1: 2-5-(4-Chlorophenyl)-1-(4-(2-quinolyl)methoxyphenyl)-pyrazol-3-yl!aceticacid.
 5. The compound according to claim 1:3-{5-(4-Chlorophenyl)-N-hydroxy-N-methyl-1-4-(2-quinolyl)methoxyphenyl!pyrazol-3-yl}propanamide.
 6. The compoundaccording to claim 1:5-(4-Chlorophenyl)-3-oximinopropyl-1-(4-(2-quinolyl)methoxy)phenyl)-pyrazol-3-yl!propanal.0.25Hydrate.
 7. The compound according to claim 1: 2-5-(4-Chlorophenyl)-1-(4-(2-quinolyl)methoxy)phenyl)-pyrazol-3-yl!ethanol.8. A pharmaceutical composition for treating inflammatory relateddisorders comprising a compound of claim 1 in association with one ormore pharmaceutically acceptable carriers.
 9. A method of treatinginflammatory related disorders in humans comprising administering to ahuman in need of such treatment an effective amount of a compound ofclaim 1.